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Retinitis pigmentosa

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Retinitis pigmentosa
SpecialtyOphthalmology Edit this on Wikidata
Normal vision. Courtesy NIH National Eye Institute
The same view with tunnel vision from retinitis pigmentosa. The blackness surrounding the central image does not indicate darkness, but rather a lack of perceived visual information.

Retinitis pigmentosa (RP) is a group of genetic eye conditions that leads to incurable blindness.[1] In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some sight all their lives.[2] Others go completely blind from RP, in some cases as early as childhood. Progression of RP is different in each case.

RP is a type of progressive retinal dystrophy, a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina lead to progressive visual loss. Affected individuals first experience defective dark adaptation or nyctalopia (night blindness), followed by reduction of the peripheral visual field (known as tunnel vision) and, sometimes, loss of central vision late in the course of the disease.

Signs

Mottling of the retinal pigment epithelium with black bone-spicule pigmentation is typically indicative (or pathognomonic) of retinitis pigmentosa. Other ocular features include waxy pallor of the optic nerve head, attenuation (thinning) of the retinal vessels, cellophane maculopathy, cystic macular edema and posterior subcapsular cataract.

Diagnosis

The diagnosis of retinitis pigmentosa relies upon documentation of progressive loss in photoreceptor cell function by electroretinography (ERG) and visual field testing.

The mode of inheritance of RP is determined by family history. At least 35 different genes or loci are known to cause "nonsyndromic RP" (RP that is not the result of another disease or part of a wider syndrome).

DNA testing is available on a clinical basis for:

  • RLBP1 (autosomal recessive, Bothnia type RP)
  • RP1 (autosomal dominant, RP1)
  • RHO (autosomal dominant, RP4)
  • RDS (autosomal dominant, RP7)
  • PRPF8 (autosomal dominant, RP13)
  • PRPF3 (autosomal dominant, RP18)
  • CRB1 (autosomal recessive, RP12)
  • ABCA4 (autosomal recessive, RP19)
  • RPE65 (autosomal recessive, RP20)

For all other genes, molecular genetic testing is available on a research basis only.

RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP can be either recessive, affecting primarily only males, or dominant, affecting both males and females, although males are usually more mildly affected. Some digenic (controlled by two genes) and mitochondrial forms have also been described.

Genetic counseling depends on an accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing.

Associations

Retinitis pigmentosa is seen in a variety of diseases, so the differential of this sign alone is broad.

  • RP combined with deafness (congenital or progressive) is called Usher syndrome.
  • RP combined with opthalmoplegia, dysphagia, ataxia, and cardiac conduction defects is seen in the mitochondrial DNA disorder Kearns-Sayre syndrome (aka Ragged Red Fiber Myopathy)
  • RP combined with retardation, peripheral neuropathy, acanthotic (spiked) RBCs, ataxia, steatorrhea, is absence of VLDL is seen in abetalipoproteinemia.

Other conditions include neurosyphilis, toxoplasmosis(Emedicine "Retinitis Pigmentosa") and Refsum's disease.

Genetics

Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration.[3] This disorder is characterized by the progressive loss of photoreceptor cells and may eventually lead to blindness.[4]

There are multiple genes that, when mutated, can cause the Retinitis pigmentosa phenotype.[5] In 1989, a mutation of the gene for rhodopsin, a pigment that plays an essential part in the visual transduction cascade enabling vision in low-light conditions, was identified. Since then, more than 100 mutations have been found in this gene, accounting for 15% of all types of retinal degeneration. Most of those mutations are missense mutations and inherited mostly in a dominant manner.

Types include:

OMIM Gene Type
Template:OMIM2 RP1 Retinitis pigmentosa-1
Template:OMIM2 RP2 Retinitis pigmentosa-2
Template:OMIM2 RPGR Retinitis pigmentosa-3
Template:OMIM2 PRPH2 Retinitis pigmentosa-7
Template:OMIM2 RP9 Retinitis pigmentosa-9
Template:OMIM2 IMPDH1 Retinitis pigmentosa-10
Template:OMIM2 PRPF31 Retinitis pigmentosa-11
Template:OMIM2 CRB1 Retinitis pigmentosa-12, autosomal recessive
Template:OMIM2 PRPF8 Retinitis pigmentosa-13
Template:OMIM2 TULP1 Retinitis pigmentosa-14
Template:OMIM2 CA4 Retinitis pigmentosa-17
Template:OMIM2 HPRP3 Retinitis pigmentosa-18
Template:OMIM2 ABCA4 Retinitis pigmentosa-19
Template:OMIM2 EYS Retinitis pigmentosa-25
Template:OMIM2 CERKL Retinitis pigmentosa-26
Template:OMIM2 FSCN2 Retinitis pigmentosa-30
Template:OMIM2 TOPORS Retinitis pigmentosa-31
Template:OMIM2 SNRNP200 Retinitis pigmentosa 33
Template:OMIM2 SEMA4A Retinitis pigmentosa-35
Template:OMIM2 PRCD Retinitis pigmentosa-36
Template:OMIM2 NR2E3 Retinitis pigmentosa-37
Template:OMIM2 MERTK Retinitis pigmentosa-38
Template:OMIM2 USH2A Retinitis pigmentosa-39
Template:OMIM2 PROM1 Retinitis pigmentosa-41
Template:OMIM2 KLHL7 Retinitis pigmentosa-42
Template:OMIM2 CNGB1 Retinitis pigmentosa-45
Template:OMIM2 BEST1 Retinitis pigmentosa-50
Template:OMIM2 TTC8 Retinitis pigmentosa 51
Template:OMIM2 C2orf71 Retinitis pigmentosa 54
Template:OMIM2 ARL6 Retinitis pigmentosa 55
Template:OMIM2 ZNF513 Retinitis pigmentosa 58
Template:OMIM2 BEST1 Retinitis pigmentosa, concentric
Template:OMIM2 PRPH2 Retinitis pigmentosa, digenic
Template:OMIM2 LRAT Retinitis pigmentosa, juvenile
Template:OMIM2 SPATA7 Retinitis pigmentosa, juvenile, autosomal recessive
Template:OMIM2 CRX Retinitis pigmentosa, late-onset dominant
Template:OMIM2 RPGR Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness

The rhodopsin gene encodes a principal protein of photoreceptor outer segments. Studies show that mutations in this gene are responsible for approximately 25% of autosomal dominant forms of RP.[3][6]

Mutations in four pre-mRNA splicing factors are known to cause autosomal dominant retinitis pigmentosa. These are PRPF3, PRPF8, PRPF31 and PAP1. These factors are ubiquitously expressed and it is still a puzzle as to why defects in a ubiquitous factor should only cause disease in the retina.

Up to 150 mutations have been reported to date in the opsin gene associated with the RP since the Pro23His mutation in the intradiscal domain of the protein was first reported in 1990. These mutations are found throughout the opsin gene and are distributed along the three domains of the protein (the intradiscal, transmembrane, and cytoplasmic domains). One of the main biochemical causes of RP in the case of rhodopsin mutations is protein misfolding, and molecular chaperones have also been involved in RP.[7] It was found that the mutation of codon 23 in the rhodopsin gene, in which proline is changed to histidine, accounts for the largest fraction of rhodopsin mutations in the United States. Several other studies have reported other mutations which also correlate with the disease. These mutations include Thr58Arg, Pro347Leu, Pro347Ser, as well as deletion of Ile-255.[6][8][9] [10] [11] In 2000, a rare mutation in codon 23 was reported causing autosomal dominant retinitis pigmentosa, in which proline changed to alanine. However, this study showed that the retinal dystrophy associated with this mutation was characteristically mild in presentation and course. Furthermore, there was greater preservation in electroretinography amplitudes than the more prevalent Pro23His mutation.[12]

Treatment

Currently there is no treatment for Retinitis Pigmentosa. The progression of the disease can be reduced by the daily intake of 15000 IU (equivalent to 4.5 mg) of vitamin A palmitate in some patients.[13] Recent studies have shown that proper vitamin A supplementation can postpone blindness by up to 10 years (by reducing the 10% loss pa to 8.3% pa) in some patients in certain stages of the disease.[14]

Research on possible treatments

Future treatments may involve retinal transplants, artificial retinal implants,[15] gene therapy, stem cells, nutritional supplements, and/or drug therapies.

2006: Stem cells: UK Researchers working with mice, transplanted mouse stem cells which were at an advanced stage of development, and already programmed to develop into photoreceptor cells, into mice that had been genetically induced to mimic the human conditions of retinitis pigmentosa and age-related macular degeneration. These photoreceptors developed and made the necessary neural connections to the animal's retinal nerve cells, a key step in the restoration of sight. Previously it was believed that the mature retina has no regenerative ability. This research may in the future lead to using transplants in humans to relieve blindness.[16]

2008: Scientists at the Osaka Bioscience Institute have identified a protein, named Pikachurin, which they believe could lead to a treatment for retinitis pigmentosa.[17][18]

2010: A possible gene therapy seems to work in mice.[1]

2010:R-Tech Ueno(Japanese Medicine manufacture enterprise )Completes Phase II Clinical Study on Ophthalmic Solution UF-021 (Product Name Ocuseva (TM)) on Retinitis Pigmentosa

Also see Wikipedia entry on TUDCA

Notable people with RP

See also

References

  1. ^ a b "Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis pigmentosa".
  2. ^ Koenekoop, R.K. (2003). Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families. American journal of ophthalmology 136(4), pp. 678-68
  3. ^ a b Hartong DT, Berson EL, Dryja TP (2006). "Retinitis pigmentosa". Lancet. 368 (9549): 1795–809. doi:10.1016/S0140-6736(06)69740-7. PMID 17113430. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Farrar GJ, Kenna PF, Humphries P (2002). "On the genetics of retinitis pigmentosa and on mutation-independent approaches to therapeutic intervention". EMBO J. 21 (5): 857–64. doi:10.1093/emboj/21.5.857. PMC 125887. PMID 11867514. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Online Mendelian Inheritance in Man (OMIM): RETINITIS PIGMENTOSA; RP - 268000
  6. ^ a b Berson EL, Rosner B, Sandberg MA, Dryja TP (1991). "Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His)". Arch. Ophthalmol. 109 (1): 92–101. PMID 1987956. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Senin II, Bosch L, Ramon E; et al. (2006). "Ca2+/recoverin dependent regulation of phosphorylation of the rhodopsin mutant R135L associated with retinitis pigmentosa". Biochem. Biophys. Res. Commun. 349 (1): 345–52. doi:10.1016/j.bbrc.2006.08.048. PMID 16934219. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Dryja TP, McGee TL, Reichel E; et al. (1990). "A point mutation of the rhodopsin gene in one form of retinitis pigmentosa". Nature. 343 (6256): 364–6. doi:10.1038/343364a0. PMID 2137202. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Dryja TP, McGee TL, Hahn LB; et al. (1990). "Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa". N. Engl. J. Med. 323 (19): 1302–7. doi:10.1056/NEJM199011083231903. PMID 2215617. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Berson EL, Rosner B, Sandberg MA, Weigel-DiFranco C, Dryja TP (1991). "Ocular findings in patients with autosomal dominant retinitis pigmentosa and rhodopsin, proline-347-leucine". Am. J. Ophthalmol. 111 (5): 614–23. PMID 2021172. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Inglehearn CF, Bashir R, Lester DH, Jay M, Bird AC, Bhattacharya SS (1991). "A 3-bp deletion in the rhodopsin gene in a family with autosomal dominant retinitis pigmentosa". Am. J. Hum. Genet. 48 (1): 26–30. PMC 1682750. PMID 1985460. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Oh KT, Weleber RG, Lotery A, Oh DM, Billingslea AM, Stone EM (2000). "Description of a new mutation in rhodopsin, Pro23Ala, and comparison with electroretinographic and clinical characteristics of the Pro23His mutation". Arch. Ophthalmol. 118 (9): 1269–76. PMID 10980774. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Berson EL, Rosner B, Sandberg MA; et al. (1993). "A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa". Arch. Ophthalmol. 111 (6): 761–72. PMID 8512476. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  14. ^ Berson EL (2007). "Long-term visual prognoses in patients with retinitis pigmentosa: the Ludwig von Sallmann lecture". Exp. Eye Res. 85 (1): 7–14. doi:10.1016/j.exer.2007.03.001. PMC 2892386. PMID 17531222.This is not verified by many Doctors
  15. ^ "Ophthalmologists Implant Five Patients with Artificial Silicon Retina Microchip To Treat Vision Loss from Retinitis Pigmentosa" (Press release). Rush University Medical Center. 2005-01-31. Retrieved 2007-06-16.
  16. ^ MacLaren, RE (2006-11-09). "Retinal repair by transplantation of photoreceptor precursors". Nature. 444 (7116): 203–7. doi:10.1038/nature05161. PMID 17093405. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  17. ^ Sato S, Omori Y, Katoh K; et al. (2008). "Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation". Nat. Neurosci. 11 (8): 923–931. doi:10.1038/nn.2160. PMID 18641643. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Lightning-Fast Vision Protein Named After Pikachu July 24, 2008
  19. ^ "CSI Cast: Jon Wellner". CBS. Retrieved October 5, 2010.
  20. ^ http://www.newyorker.com/archive/2006/10/23/061023ta_talk_paumgarten
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